NM_002124.4:c.764-2A>G

Variant names:

• chr6-32580272-T-C
• rs756519999
• NM_002124.4:c.764-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_002124.4(HLA-DRB1):​c.764-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 15)
  • Exomes 𝑓: 0.0000074 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB1 NM_002124.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.34
• Publications: 1 publications found

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa. It is encoded by 6 exons. Exon one encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain; and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

HLA-DRB1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.029962547 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of -26, new splice context is: ttgcttcaataacttttaAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 6-32580272-T-C is Pathogenic according to our data. Variant chr6-32580272-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3065325.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.764-2A>G		splice_acceptor intron	N/A	NP_002115.2	P01911

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.764-2A>G		splice_acceptor intron	N/A	ENSP00000353099.5	P01911
	HLA-DRB1	ENST00000963203.1		c.842-2A>G		splice_acceptor intron	N/A	ENSP00000633262.1
	HLA-DRB1	ENST00000859900.1		c.763+474A>G		intron	N/A	ENSP00000529959.1

Frequencies

GnomAD3 genomes AF: 0.0000184 AC: 2 AN: 108600 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000398

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000504 AC: 1 AN: 198490 AF XY: 0.00000919

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000532

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000743 AC: 7 AN: 941646 Hom.: 0 Cov.: 14 AF XY: 0.00000830 AC XY: 4 AN XY: 481896

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24946

American (AMR) AF: 0.00 AC: 0 AN: 32580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18782

East Asian (EAS) AF: 0.00 AC: 0 AN: 26356

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69310

European-Finnish (FIN) AF: 0.0000872 AC: 4 AN: 45882

Middle Eastern (MID) AF: 0.000254 AC: 1 AN: 3932

European-Non Finnish (NFE) AF: 0.00000147 AC: 1 AN: 679176

Other (OTH) AF: 0.00 AC: 0 AN: 40682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000184 AC: 2 AN: 108724 Hom.: 0 Cov.: 15 AF XY: 0.0000379 AC XY: 2 AN XY: 52764

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30854

American (AMR) AF: 0.00 AC: 0 AN: 9232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2418

East Asian (EAS) AF: 0.00 AC: 0 AN: 3098

South Asian (SAS) AF: 0.00 AC: 0 AN: 3084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.0000398 AC: 2 AN: 50286

Other (OTH) AF: 0.00 AC: 0 AN: 1416

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0260 Hom.: 0

ExAC AF: 0.00165 AC: 193

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple sclerosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	32
DANN	Benign	0.85
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.64	D
PhyloP100		3.3
GERP RS		2.9
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -19
DS_AL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756519999; hg19: chr6-32548049; COSMIC: COSV106063193;